Challenging selective vulnerability in Parkinson's disease: a systematic review and meta-analysis
- 1UK DRI at Imperial College London, Department of Brain Sciences, London, UK
Abstract
Selective vulnerability is widely assumed in Parkinson's disease (PD), but whether dopaminergic neurons of the substantia nigra are uniquely vulnerable has not been established. Explanations of neuronal degeneration in Parkinson's disease often centre on the distinctive properties of substantia nigra dopaminergic neurons. Whether these properties are necessary for substantial neuronal loss remains unclear. We preregistered a systematic review of 166 post-mortem case-control studies published between 1963 and 2025 and synthesised neuronal counts and densities from 152 studies using a multilevel meta-analysis. After six decades, only 18% of countable brain atlas labels had been examined, and most populations were represented by a single study. Substantial loss beyond dopaminergic and classically pigmented populations shows that neither dopaminergic identity nor neuromelanin is necessary for marked degeneration, challenging key tenets of selective vulnerability in PD. Comparisons across other anatomical and physiological features remain limited by sparse sampling and uncertainty. We identify less-studied populations with substantial estimated loss and estimate the additional sampling needed to improve precision under specified assumptions. These findings direct replication and comparative counting towards uncertainties that limit explanations of neuronal loss across affected and potentially spared populations.
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BibTeX
@misc{lunt2026challenging,
title = {{Challenging selective vulnerability in Parkinson's disease: a systematic review and meta-analysis}},
author = {W. Lunt and J. A. Moore and E. Cottard and A. E. Murphy and M. Shah and J. Sang and J. Choi and H. Dash and S. Dawson and N. Green and E. Nagaeva and S. Burke and J. P. T. Higgins and N. G. Skene},
howpublished = {bioRxiv},
year = {2026},
month = may,
doi = {10.64898/2026.05.13.724902},
url = {https://www.biorxiv.org/content/10.64898/2026.05.13.724902v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Challenging selective vulnerability in Parkinson's disease: a systematic review and meta-analysis
AU - W. Lunt
AU - J. A. Moore
AU - E. Cottard
AU - A. E. Murphy
AU - M. Shah
AU - J. Sang
AU - J. Choi
AU - H. Dash
AU - S. Dawson
AU - N. Green
AU - E. Nagaeva
AU - S. Burke
AU - J. P. T. Higgins
AU - N. G. Skene
PY - 2026
DA - 2026/05/13
PB - bioRxiv
DO - 10.64898/2026.05.13.724902
UR - https://www.biorxiv.org/content/10.64898/2026.05.13.724902v2
AB - Selective vulnerability is widely assumed in Parkinson's disease (PD), but whether dopaminergic neurons of the substantia nigra are uniquely vulnerable has not been established. Explanations of neuronal degeneration in Parkinson's disease often centre on the distinctive properties of substantia nigra dopaminergic neurons. Whether these properties are necessary for substantial neuronal loss remains unclear. We preregistered a systematic review of 166 post-mortem case-control studies published between 1963 and 2025 and synthesised neuronal counts and densities from 152 studies using a multilevel meta-analysis. After six decades, only 18% of countable brain atlas labels had been examined, and most populations were represented by a single study. Substantial loss beyond dopaminergic and classically pigmented populations shows that neither dopaminergic identity nor neuromelanin is necessary for marked degeneration, challenging key tenets of selective vulnerability in PD. Comparisons across other anatomical and physiological features remain limited by sparse sampling and uncertainty. We identify less-studied populations with substantial estimated loss and estimate the additional sampling needed to improve precision under specified assumptions. These findings direct replication and comparative counting towards uncertainties that limit explanations of neuronal loss across affected and potentially spared populations.
ER -